TY - JOUR
T1 - Squamous cell carcinoma-related oncogene (SCCRO) family members regulate cell growth and Proliferation through their cooperative and antagonistic effects on cullin neddylation
AU - Fu, Weimin
AU - Sun, Joanne
AU - Huang, Guochang
AU - Liu, Jeffrey C.
AU - Kaufman, Andrew
AU - Ryan, Russell J.H.
AU - Ramanathan, Suresh Y.
AU - Venkatesh, Tadmiri
AU - Singh, Bhuvanesh
N1 - © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/3/18
Y1 - 2016/3/18
N2 - SCCRO (squamous cell carcinoma-related oncogene; also known as DCUN1D1) is a highly conserved gene that functions as an E3 in neddylation. Although inactivation of SCCRO in yeast results in lethality, SCCRO mice are viable. The exclusive presence of highly conserved paralogues in higher organisms led us to assess whether compensation by SCCRO paralogues rescues lethality in SCCRO mice. Using murine and Drosophila models, we assessed the in vivo activities of SCCRO and its paralogues in cullin neddylation. We found that SCCRO family members have overlapping and antagonistic activity that regulates neddylation and cell proliferation activities in vivo. In flies, both dSCCRO and dSCCRO3 promote neddylation and cell proliferation, whereas dSCCRO4 negatively regulates these processes. Analysis of somatic clones showed that the effects that these paralogues have on proliferation serve to promote cell competition, leading to apoptosis in clones with a net decrease in neddylation activity.Wefound that dSCCRO and, to a lesser extent, dSCCRO3 rescue the neddylation and proliferation defects promoted by expression of SCCRO4. dSCCRO and dSCCRO3 functioned cooperatively, with their coexpression resulting in an increase in both the neddylated cullin fraction and proliferation activity. In contrast, human SCCRO and SCCRO4 promote, and human SCCRO3 inhibits, neddylation and proliferation when expressed in flies. Our findings provide the first insights into the mechanisms through which SCCRO family members cooperatively regulate neddylation and cell proliferation.
AB - SCCRO (squamous cell carcinoma-related oncogene; also known as DCUN1D1) is a highly conserved gene that functions as an E3 in neddylation. Although inactivation of SCCRO in yeast results in lethality, SCCRO mice are viable. The exclusive presence of highly conserved paralogues in higher organisms led us to assess whether compensation by SCCRO paralogues rescues lethality in SCCRO mice. Using murine and Drosophila models, we assessed the in vivo activities of SCCRO and its paralogues in cullin neddylation. We found that SCCRO family members have overlapping and antagonistic activity that regulates neddylation and cell proliferation activities in vivo. In flies, both dSCCRO and dSCCRO3 promote neddylation and cell proliferation, whereas dSCCRO4 negatively regulates these processes. Analysis of somatic clones showed that the effects that these paralogues have on proliferation serve to promote cell competition, leading to apoptosis in clones with a net decrease in neddylation activity.Wefound that dSCCRO and, to a lesser extent, dSCCRO3 rescue the neddylation and proliferation defects promoted by expression of SCCRO4. dSCCRO and dSCCRO3 functioned cooperatively, with their coexpression resulting in an increase in both the neddylated cullin fraction and proliferation activity. In contrast, human SCCRO and SCCRO4 promote, and human SCCRO3 inhibits, neddylation and proliferation when expressed in flies. Our findings provide the first insights into the mechanisms through which SCCRO family members cooperatively regulate neddylation and cell proliferation.
KW - Animals
KW - Cell Proliferation
KW - Cullin Proteins/metabolism
KW - Drosophila Proteins/physiology
KW - Drosophila melanogaster
KW - Female
KW - HeLa Cells
KW - Humans
KW - Intracellular Signaling Peptides and Proteins
KW - Male
KW - Mice, Knockout
KW - Organ Specificity
KW - Protein Processing, Post-Translational
KW - Proto-Oncogene Proteins/physiology
UR - http://www.scopus.com/inward/record.url?scp=84964868205&partnerID=8YFLogxK
U2 - 10.1074/jbc.M115.692756
DO - 10.1074/jbc.M115.692756
M3 - Article
C2 - 26792857
AN - SCOPUS:84964868205
SN - 0021-9258
VL - 291
SP - 6200
EP - 6217
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 12
ER -